Citation for published version (APA): Douma, R. A. (2010). Pulmonary embolism: advances in diagnosis and prognosis

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1 UvA-DARE (Digital Academic Repository) Pulmonary embolism: advances in diagnosis and prognosis Douma, R.A. Link to publication Citation for published version (APA): Douma, R. A. (2010). Pulmonary embolism: advances in diagnosis and prognosis General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 28 Sep 2018

2 Chapter 6 Potential of an ageadjusted D-dimer cutoff value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts Renée A. Douma, Grégoire le Gal, Maaike Söhne, Marc Righini, Pieter W. Kamphuisen, Arnaud Perrier, Marieke J.H.A. Kruip, Henri Bounameaux, Harry R. Büller, Pierre-Marie Roy British Medical Journal 2010;340:c1475

3 Chapter 6 ABSTRACT Objective In older patients, the D-Dimer test has reduced specificity and is therefore less useful. In this study a new, age dependent cut-off value for the D-dimer test for the test was devised ant its usefulness with older patients assessed. Design Retrospective multicenter cohort study. Setting General and teaching hospitals in Belgium, France, the Netherlands and Switzerland. Patients 5132 consecutive patients with clinically suspected PE. Intervention Development of a new D-dimer cut-off point in patients older than 50 years in a derivation set (data from two multicenter cohort studies), based on receiver operating characteristics (ROC)- curves. This cut-off was then validated with two independent validation datasets. Main outcome measures The proportion of patients in the validation cohorts with a negative D-dimer test, the proportion in whom PE could be excluded and the false-negative rates. Results The new D-dimer cut-off value was defined as (patient s age x 10) µg/l in patients >50 years. In 1331 patients with an unlikely score from clinical probability assessment, PE could be excluded in 42% with the new cut-off value versus 36% using the old cut-off value (<500µg/L). In the validation sets, the increase in the proportion of patients with a D-dimer below the new cut-off value compared with the old value was 5% and 6%. This absolute increase was largest among patients >70 years, ranging from 13% to 16% in the three datasets. The failure rates (all ages) were 0.2% (95%CI 0.0 to 1.0) in the derivation set and 0.6% (0.3 to1.3%) and 0.3% (0.1 to1.1%) in the two validation sets. Conclusions The age adjusted D-dimer cut-off point, combined with clinical probability, greatly increases the proportion of older patients in whom PE could be safely excluded. 96

4 Potential of an age-adjusted D-dimer cut-off value to improve the exclusion of PE in older patients INTRODUCTION Measurement of D-dimer concentration in the blood is a valuable tool in the diagnostic investigation of patients with suspected pulmonary embolism (PE). A D-dimer concentration below the conventional cut-off point of 500 µg/l combined with a low/intermediate or unlikely clinical probability can safely rule out the diagnosis in approximately 30% of patients with suspected PE (1-3). However, the D-dimer concentration increases with age and its specificity for PE decreases, which makes the test less useful to exclude PE in older patients (4-9). Indeed, the test is able to rule out PE in 60% of patients aged less than 40 years, but in only 5% of patients above the age of 80 (8). If the D-dimer is combined with an unlikely clinical probability (10) to rule out PE, 10% of patients above 75 years versus 32% of patients of all ages do not need further diagnostic testing; the number needed to test for 1 negative test result is 10.6 and 3.1, respectively (9). Raising the cut-off value to various points between 600 µg/l and 1000 µg/l increased specificity, but this came at the cost of safety, with more false negative test results (11). In this analysis, however, no stratification was made for clinical probability. By constructing receiver operating characteristic (ROC) curves, we derived a new age dependent D-dimer cut-off value and analyzed its safety and clinical utility in combination with clinical probability assessment, for the exclusion of PE in two large prospective cohort studies in patients with suspected PE. We then validated the outcome in two other large management studies. METHODS Derivation set We analyzed the combined data from two prospective multicenter cohort studies, which included 1721 consecutive outpatients with suspected PE (1,12). These outcome studies were designed to evaluate diagnostic strategies for PE, combining clinical probability assessment, D- Dimer measurement, lower limb venous compression ultrasonography, and helical computed tomography (CT). Briefly, all consecutive patients admitted to the emergency department of four general and teaching hospitals were included if they had a clinical suspicion of PE. The inclusion and exclusion criteria and the results of the two studies have been published previously (1,12). The first study (12), conducted at the Geneva University Hospital, the Centre Hospitalier Universitaire Vaudois, Lausanne, both in Switzerland, and the Angers University Hospital in Angers, France, between October 2000 and June 2002,comprised 965 patients. The second study (1), conducted at the Geneva University Hospital, Switzerland, the Angers University Hospital, and the Hôpital Européen Georges Pompidou, Paris, France, between September 2002 and October 2003, comprised 756 patients. Both studies were approved by the 97

5 Chapter 6 institutional review boards of each participating institution and written informed consent was obtained from all patients. All patients underwent a sequential diagnostic investigation, including plasma D-Dimer measurement by an enzyme-linked immunosorbent assay (rapid ELISA assay, VIDAS D-Dimer Exclusion, Biomérieux, Marcy-l Etoile, France). For each patient, the Geneva score (13) was assessed to assign the patient to a clinical probability category with possible override by implicit assessment in case of disagreement with the assessor s clinical judgment (14). Variables included in the Wells clinical prediction rule for PE (10) were also systematically and prospectively collected, allowing calculation of the Wells score. PE was ruled out by: (a) a D-Dimer concentration below the cut-off value of 500 µg/l, except in patients with high clinical probability patients, in the second study; (b) negative results from lower limb venous compression ultrasonography and from helical CT in patients with a low or intermediate clinical probability of PE; or (c) by a normal ventilation-perfusion lung scan or a normal pulmonary angiogram in patients with a high clinical probability or with inconclusive helical CT. PE was established by: (a) finding a proximal deep vein thrombosis on lower limb ultrasonography; (b) a positive result from helical CT; (c) a high-probability ventilationperfusion lung scan or a positive pulmonary angiogram in high clinical probability patients with negative results from both compression ultrasonography and helical CT, and in patients with inconclusive CT. Patients were followed up by their family physicians and were interviewed by telephone by one of the study coordinators at the end of a three months follow-up. The outcome was an estimate of the three month thromboembolic risk in patients in whom pulmonary embolism was considered ruled out by the initial diagnostic work-up and who did not receive anticoagulants during follow-up. Confirmation of venous thromboembolic events during follow-up were established with the usual criteria (1,2,12). Validation set 1 For the first validation set, data from a third prospective multicenter cohort study were used (2). This study evaluated the clinical effectiveness of a simplified algorithm using the dichotomized Wells rule, D-dimer testing, and CT in patients with suspected PE. Briefly, all consecutive inpatients and outpatients with clinically suspected acute pulmonary embolism were eligible for the study, which was conducted between November 2002 and August 2004 in 12 hospitals in the Netherlands. The institutional review boards of all participating hospitals approved the study protocol. The results, and the inclusion and exclusion criteria were published previously (2). The study population comprised 3306 patients. All patients underwent a sequential diagnostic investigation, consisting of clinical probability calculation, a D-dimer test (Tinaquant, Roche Diagnostica, Mannheim, Germany or Vidas D- dimer Exclusion, Biomerieux, Marcy-l Etoile, France) and CT scanning. At admission, the clinical probability was calculated by the treating physician using the Wells score. According to 98

6 Potential of an age-adjusted D-dimer cut-off value to improve the exclusion of PE in older patients the protocol, a D-dimer test was performed only in patients with a Wells score of 4. Pulmonary embolism was ruled out by (a) an unlikely clinical probability (Wells score 4) combined with a D-dimer test 500 μg/l or (b) a negative helical CT in patients with a likely clinical probability or an abnormal D-dimer test. Pulmonary embolism was established by a positive helical CT. The follow-up was performed the same way as in the derivation set studies. Validation set 2 For the second validation set, data from a fourth prospective multicenter study was used (3). This study investigated in a randomized non-inferiority trial whether the addition of venous ultrasonography to multi-detector CT (MDCT) improved the detection of PE. Consecutive outpatients with clinically suspected acute pulmonary embolism were eligible for the study, which was conducted between January 2005 and August 2006 in six hospitals in France, Belgium and Switzerland. The institutional review boards of all participating hospitals approved the study protocol. The results and inclusion and exclusion criteria were published previously (8). The study population comprised 1812 patients. All patients underwent a sequential diagnostic investigation, consisting of clinical probability calculation, a D-dimer test (Vidas D-dimer Exclusion, Biomerieux, Marcy-l Etoile, France) and then randomization to either MDCT alone, or compression ultrasonography (CUS) of the legs followed by MDCT. At admission, the clinical probability was calculated by the treating physician using the revised Geneva score (RGS) (15). Pulmonary embolism was ruled out by (a) a non-high clinical probability (RGS < 11) combined with a D-dimer test < 500 μg/l or (b) a negative helical CT result in patients with a high RGS or an abnormal D-dimer test result. Pulmonary embolism was established by a positive helical CT or CUS. The follow-up was performed the same way as in the previous studies. Data analysis In the derivation set and validation set 1 the Wells clinical prediction rule for PE was calculated in all patients, and patients were classified according to the dichotomized Wells score as likely or unlikely to have PE. In validation set 2, the RGS was calculated in all patients and classified as a high or non-high (low or intermediate) RGS. To derive a new cut-off value, we divided patients aged >50 in the derivation set into 10 year age groups. We constructed Receiver Operating Characteristic (ROC) curves of the D-dimer test for each age group to find the best cut-off value (with a sensitivity of 100% and highest corresponding specificity). We plotted the D-dimer cut-off level against age group and performed linear regression analysis to obtain the regression coefficient, representing the increase in D-dimer cut-off value per decade. This coefficient was divided by 10 to find the coefficient per year. This coefficient was the multiplication factor for age in the new ageadjusted cut-off value. 99

7 Chapter 6 We then calculated the proportion of patients with a negative D-Dimer test result, as defined by the new cut-off point), the proportion in whom PE could be excluded (based on an unlikely Wells score or non-high RGS plus the negative D-dimer test result), and the false negative rates (that is, those patients who had PE in the diagnostic investigation or during follow-up). The number of patients needed to test by D-Dimer to rule out one PE was computed as 1 divided by the proportion of patients with negative D-Dimer test result in each age group (16). In the validation sets, D-dimer test results were missing in a large proportion of patients with a likely Wells score (2) or high RGS (3). Therefore, the age-adjusted D-dimer cut-off point was validated only in patients with an unlikely or non-high clinical probability in these two cohorts. Exact 95% confidence intervals (CI) were calculated using CIA software version 1.0 (Gardner et al. Confidence Interval Analysis (CIA), BMJ Books). All other analyses were performed using SPSS version 15.0 (SPSS, Chicago IL, USA). RESULTS Derivation of the new cut-off value Of the 1721 patients included in the derivation set, 416 (24.2%) had PE. The D-Dimer test was not performed in nine patients from the second study with high clinical probability (all nine had PE diagnosed during initial diagnostic investigation). Table 1 shows the clinical characteristics of the patients in the derivation cohort. Table 1. Baseline characteristics of the derivation and validation cohorts of patients with clinically suspected pulmonary embolism (PE) used to produce an age dependent cut-off value for the D-dimer test for PE. Values are numbers (percentage) of patients unless specified otherwise. Characteristics Derivation set (n=1721) Validation set 1 (n=3306) Validation set 2 (n=1819) Age in years, mean (SD) 61 (19) 53 (18) 59 (19) Age in years, median (interquartile range) 63 (45-76) 51 (39-68) 61 (45-75) Female 1016 (59) 1896 (57) 922 (51) History of venous thromboembolism 308 (18) 480 (15) 300 (17) Active malignancy 164 (10) 474 (14) 127 (7.0) Recent surgery 94 (5.5) 46 (1.4) 94 (5.2) Hemoptysis 80 (4.6) 176 (5.3) 83 (4.6) Heart rate >100 beats/min 362 (21) 867 (26) 369 (20) Clinical signs of deep vein thrombosis 246 (14) 190 (5.7) 153 (8.4) 100

8 Potential of an age-adjusted D-dimer cut-off value to improve the exclusion of PE in older patients Figure 1. Optimal cut-off values for D- dimer test for pulmonary embolism by age in patients with an unlikely clinical probability for pulmonary embolism (sensitivity set at 100%). The figure shows the increase in optimal D-dimer cut-off value per patient age group, obtained from the ROC curves for each group. The cut-off point increased from 512 µg/l in patients <50 years old to 934 µg/l in patients > 80 years old. The regression coefficient was 112 (SE 12.03) µg/l increase per decade, or 11.2 µg/l increase per year (r 2 = 0.966). To be conservative and to facilitate clinical usefulness and practicality, we considered a 10 µg/l increase per patient year to be an appropriate new D-dimer coefficient. Starting from the conventional cut-off of 500 µg/l until the age of 50, for older patients the age should be multiplied by 10 to calculate the age-adjusted cut-off value. Derivation set outcome With the conventional cut-off value, the VIDAS D-Dimer test was normal (<500 µg/l) in 512/1712 patients (29.9%), and none had PE during the initial investigation or the three month follow-up period (0.0%, 95% CI 0 to 0.7%). The number of patients needed to test to find one normal D-dimer test result was 3.3. The Wells score could not be computed 54 of the patients, mainly because information on the likelihood of an alternative diagnosis to that of PE was missing (n=42). Using the age adjusted cut-off value ((age (years)x10) µg/l) we found that D-dimer test results were negative in 615/1712 patients (46.2%, number needed to test 2.2). This resulted in a 20.1% (95% CI 16.9 to 23.8%) relative increase in the number of patients in whom the D-Dimer test was considered as normal. Of these 615 patients, five had PE during investigation or three month follow-up (0.8%, 95% CI 0.4 to 1.9%). Table 2 shows the proportion of the 1331 patients with an unlikely clinical probability in whom pulmonary embolism could be excluded based on the conventional and the age adjusted D- dimer cut-off values. There was a 17.4% (95% CI 14.3 to 21.1%) relative increase in the number of patients with a negative D-Dimer test result when the age-adjusted D-dimer cut-off value 101

9 Chapter 6 Table 2. Proportion of patients in the derivation set with an unlikely clinical probability of pulmonary embolism (PE)* in whom PE can be excluded based on a D-dimer test result below the cut-off value: comparison of different cut-off values stratified by age groups. All patients Age range (years) >80 N (%) of patients (14) 211 (16) 265 (20) 198 (15) Median (IQR) age (years) 61 (44-75) 56 (54-58) 66 (63-68) 76 (73-78) 85 (82-88) Conventional D-dimer cut-off value Patients with normal D-dimer n (%, 95%CI) 477 (36, 33-39) 97 (51, 44-58) 63 (30, 24-36) 40 (15, 11-20) 11 (6, 3-10) False negative, n, % (95% CI) 0, 0.0 (0-0.8) 0, 0.0 (0-3.8) 0, 0.0 (0-5.8) 0, 0.0 (0-8.8) 0, 0.0 (0-26) Number needed to test New D-dimer cut-off Patients with normal D-dimer n (%, 95%CI) 560 (42, 39-45) 102 (54, 47-61) 76 (36, 30-43) 75 (28, 23-34) 41 (21, 16-27) False negative, n, % (95% CI) 1, 0.2 (0-1.0) 0, 0.0 (0-3.6) 0 (0.0 (0-4.8) 1, 1.3 ( ) 0, 0.0 (0-8.6) Number needed to test Increase in percentage of patients below cut-off value Absolute (%) Relative (%) *Based on Wells clinical decision rule. Conventional cut-off value for D-dimer test = 500 µg/l, age adjusted cut-off value = (agex10) µg/l (if age>50). Number needed to test to find one normal D-dimer test result. 102

10 Potential of an age-adjusted D-dimer cut-off value to improve the exclusion of PE in older patients was used. The false negative rate was 0 (0.0%, 95% CI 0 to 0.8%) for the conventional cut-off value compared with 1 (0.2%; 95%CI 0 to 1.0%) for the age adjusted cut-off. Table 2 also shows the increase in the proportion of patients with an unlikely clinical probability in whom D-dimer levels would be considered normal for specific age groups by using the age adjusted cut-off value: this increase was highest among the oldest patient groups (>70 years), with an absolute increase of 14% compared with the conventional cut-off point. External validation The concept of using an increasing cut-off value for the D-dimer test according to age was validated in two independent cohorts of patients with suspected PE. The clinical characteristics of the patients in these cohorts were similar to those of the patients in the derivation set (Table 1). Validation set 1 Of the 3306 patients included in validation set 1, 674 had PE (20.4%). In 41 of the 2206 patients with an unlikely clinical probability of PE, D-dimer test results were recorded only qualitatively and were therefore missing for this analysis. In another seven patients age was not documented, leaving 2158 patients. Among these, 983 patients had a negative D-dimer test result with the conventional cut-off value, of whom 2 patients (0.2%, 95%CI 0.1 to 0.7%) had PE during the initial diagnostic investigation or the three month follow-up. With the age adjusted cut-off, 1093 patients had a negative D-dimer test result, of whom seve (0.6%, 95% CI 0.3 to 1.3%) had PE. Table 3 shows the proportion of patients in whom PE could be excluded based on the old and the new cut-off values. The age adjusted D-dimer cut-off resulted in an 11.2% (95% CI 9.3 to 13.3%) increase in the number of patients with a negative D-Dimer test result. The increase in the proportions of patients in whom PE could be ruled out (that is, unlikely clinical probability with a D-dimer below the cut-off) from using the age adjusted cut-off value was most prominent among patients in the age groups > 70 years, with an absolute increase of 16% (Table 3). The data for validation set 1 came from a study in which two different D-dimer tests were used. We therefore performed separate analyses for the two D-dimer tests. There was no difference between the two tests in the false negative rate for the age adjusted D-dimer cut-off value (see Table 4). Validation set 2 Of the 1812 patients included in the second validation set, 375 (20.7%) had PE. Among the 1643 patients who had a non-high RGS, 561 patients (34%, number needed to test 2.9) had a normal D-Dimer test result according to the conventional cut-off (Table 5), and none (0.0%, 95%CI 0 to 0.7%) had PE during the initial investigation or the three month follow-up. With the age adjusted cut-off value, 663/1643 patients had a negative D-Dimer test result (40.4%, 103

11 Chapter 6 Table 3. Proportion of patients in validation set 1 with an unlikely clinical probability of pulmonary embolism (PE)* in whom PE could be excluded based on a D-dimer test result below the cut-off value: comparison of different cut-off values stratified by age groups. All patients Age range (years) >80 N (%) of patients (17) 270 (13) 245 (18) 166 (7.7) Median (IQR) age (years) 49 (37-66) 55 (52-57) 66 (63-68) 74 (72-77) 84 (82-88) Conventional D-dimer cut-off value Patients with normal D-dimer n (%, 95%CI) 983 (46, 44-48) 160 (45, 40-50) 69 (26, 21-31) 40 (16, 12-22) 25 (15, 10-21) False negative, n, % (95% CI) 2, 0.2 ( ) 0, 0.0 (0-2.3) 0, 0.0 (0-5.3) 0, 0.0 (0-8.8) 0, 0.0 (0-13) Number needed to test New D-dimer cut-off Patients with normal D-dimer n (%, 95%CI) 1093 (51, 49-53) 179 (50, 45-55) 96 (36, 30-41) 81 (33, 28-39) 48 (29, 23-36) False negative, n, % (95% CI) 7, 0.6 ( ) 1 (0.6, ) 2, 2.1 ( ) 1, 1.2 ( ) 1, 2.1 (0.4-11) Number needed to test Increase in percentage of patients below cut-off value Absolute (%) Relative (%) *Based on Wells clinical decision rule. Conventional cut-off value for D-dimer test = 500 µg/l, age adjusted cut-off value = (agex10) µg/l (if age>50). Number needed to test to find one normal D-dimer test result. 104

12 Potential of an age-adjusted D-dimer cut-off value to improve the exclusion of PE in older patients Table 4. Proportion of patients in validation set 1 with an unlikely clinical probability of pulmonary embolism (PE)* in whom PE could be excluded based on a D-dimer test result below the cut-off value: comparison of the two D-dimer tests used in the set. D-dimer test Tinaquant Vidas P-value of difference Conventional cut-off value for D-dimer test Number of patients below cut-off value, N (%) 576/1204 (48) 407/954 (43) Number of patients with false negative result, N (%) 2/576 (0.3, ) 0/407 (0.0, ) >0.05 Age adjusted cut-off value for D-dimer test Number of patients below cut-off value, N (%, 95%CI) 637/1204 (53) 456/954 (48) Number of patients with false negative result, N (%, 95%CI) 4/637 (0.6, ) 3/456 (0.7, ) >0.05 *Based on Wells clinical decision rule. Conventional cut-off value for D-dimer test = 500 µg/l, age adjusted cut-off value = (agex10) µg/l (if age>50). 105

13 Chapter 6 Table 5. Proportion of patients in validation set 2 with a non-high clinical probability of pulmonary embolism (PE)* in whom PE could be excluded based on a D-dimer test result below the cut-off value: comparison of different cut-off values stratified by age groups. All patients Age range (years) >80 N (%) of patients (15) 260 (16) 333 (20) 253 (15) Median (IQR) age (years) 61 (45-75) 55 (52-57) 65 (62-67) 75 (72-77) 83 (81-86) Conventional D-dimer cut-off value Patients with normal D-dimer n (%, 95%CI) 561 (34, 32-37) 110 (44, 38-50) 79 (30, 25-36) 43 (13, 10-17) 22 (9, 6-13) False negative, n, % (95% CI) 0, 0.0 (0-0.7) 0, 0.0 (0-3.4) 0, 0.0 (0-4.6) 0, 0.0 (0-8.2) 0, 0.0 (0-15) Number needed to test New D-dimer cut-off Patients with normal D-dimer n (%, 95%CI) 663 (40, 38-43) 115 (46, 40-52) 97 (37, 32-43) 89 (27, 22-32) 54 (21, 17-27) False negative, n, % (95% CI) 2, 0.3 ( ) 1, 0.9 ( ) 0, 0.0 ( ) 1, 1.1 ( ) 0, 0.0 (0-6.6) Number needed to test Increase in percentage of patients below cut-off value Absolute (%) Relative (%) *Based on revised Geneva score. Conventional cut-off value for D-dimer test = 500 µg/l, age adjusted cut-off value = (agex10) µg/l (if age>50). Number needed to test to find one normal D-dimer test result. 106

14 Potential of an age-adjusted D-dimer cut-off value to improve the exclusion of PE in older patients number needed to test 2.5) (Table 5). This resulted in an 18.2% (95% CI 15.0 to 21.4%) increase in the number of patients in whom the D-Dimer test was considered was negative. The false negative rate with the age adjusted cut-off value was 2 (0.3%, 95% CI 0.1 to 1.1%). Again, use of the age adjusted cut-off value had the greatest effect in the older age groups (Table 5). DISCUSSION The study shows that an age-adjusted cut-off level for the D-Dimer test for exclusion of pulmonary embolism doubles the proportion of older patients (>70 years) in whom PE can be safely excluded in comparison with the conventional cut-off value of 500 µg/l. We derived and validated this new cut-off value in three large cohorts of consecutive patients with suspected PE, totalling over 5000 patients. In these three cohorts, the number of older patients in which PE could be safely ruled out was consistent, between 25% and 30%. The clinical usefulness of the new cut-off value increased significantly with age: the proportion of patients in whom PE could be ruled out with the new cut-off value was a third higher in patients older than 50 and almost twice as high in patients older than 70 compared with the conventional cut-off. Increasing the cut-off point to improve clinical utility did not come at the expense of safety: in the derivation and validation sets there was no difference in the false negative rate, and for the total population and for patients aged >50 years the 95% upper confidence levels were well below 3% with the new cut-off value. Impact in the clinical setting A recent cost effectiveness analysis showed that D-dimer measurement as part of the diagnostic investigation of patients with suspected PE was cost saving until the age of 79 years (17). After 80 years, the test s clinical utility was too low to be cost effective, and the costs of strategies with or without D-dimer testing were similar. This analysis was based on the conventional cut-off point of 500 µg/l for ELISA based assays. It can be expected, however, that the test s cost effectiveness in older patients would increase with the new cut-off value, as the number needed to test was lower with the age adjusted cut-off value compared with the conventional cut-off value in patients > 80 years old (3.5 versus 6.6). For a given clinical setting, this means that for every 35 patients aged > 80 with a low/intermediate or unlikely clinical probability for PE, imaging tests can be avoided in five patients when the conventional cut-off is used compared with 10 patients when the age adjusted cut-off value is used. Avoiding imaging tests (that is, ventilation-perfusion (V/Q) scintigraphy or CT scanning) would be of particular benefit for older patients, because of the high frequency of non-conclusive scintigraphy results, the risk from injection with iodine-contrast agent for CT scanning and the length of hospital stay when ordering imaging tests in this patient population. Some may argue that having to calculate a D-dimer cut-off value is impractical in a clinical setting, and that the new value is a series of multiple cut-off points. However, the treating 107

15 Chapter 6 physician needs to remember only the coefficient of 10 in order to calculate the new cut-off value, which is an easy multiplication. Strengths and Limitations The calculation of the age adjusted cut-off value was facilitated by the large size of the study population, which is a major strength of this analysis. However, some aspects of our study warrant comment. First, two different D-dimer assays were used in the validation cohorts. Although there was no significant difference between the two tests, and the new cut-off value performed equally well with both assays, the study may not have been sufficiently powered to detect a difference between the two. It is unknown how the new D-dimer cut-off value will perform in other D-dimer assays. Secondly, although D-dimer tests and the (variables for the) clinical decision rule were collected prospectively, this study was a retrospective analysis. After derivation and independent validation in a completely distinct cohort of patients, the next step would be to validate this cut-off prospectively in a formal outcome study with patient followup. Conclusions In conclusion, a cut-off value adjusted to age combined with clinical probability greatly increased the utility of the D-dimer test for the exclusion of PE among older patients without reducing safety. This new cut-off is therefore clinically relevant and has sustained external validation. The next step would be to validate this new D-dimer cut-off value prospectively before implementation in daily practice. REFERENCE LIST 1. Perrier A, Roy PM, Sanchez O, et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005;352: The Christopher study investigators, van Belle A, Buller HR, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295: Righini M, Le Gal G, Aujesky D, et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet 2008;371: Hager K, Platt D. Fibrin degeneration product concentrations (D-dimers) in the course of ageing. Gerontology 1995;41: Perrier A, Desmarais S, Goehring C, et al. D-dimer testing for suspected pulmonary embolism in outpatients. Am J Respir Crit Care Med 1997;156: Tardy B, Tardy-Poncet B, Viallon A, et al. Evaluation of D-dimer ELISA test in elderly patients with suspected pulmonary embolism. Thromb Haemost 1998;79: Masotti L, Ceccarelli E, Cappelli R, et al. Plasma D-dimer levels in elderly patients with suspected pulmonary embolism. Thromb Res 2000;98: Righini M, Goehring C, Bounameaux H, et al. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am J Med 2000;109:

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